Abstract:

Claims:

1. A method of treating or inhibiting arthrosis pain in a subject, said
method comprising administering to said subject a pharmacologically
effective amount of axomadol.

2. A method according to claim 1, wherein the axomadol is administered in
a solid drug form.

3. A method according to claim 1, wherein the axomadol is administered
orally.

4. A method according to claim 1, wherein the axomadol is administered
twice daily.

5. A method according to claim 1, wherein the axomadol is administered in
a dose of from 10 to 2000 mg, relative to weight of the free base.

6. A method according to claim 1, wherein the axomadol is administered in
the form of a hydrochloride salt.

7. A method according to claim 1, wherein said subject is a subject
suffering from an arthrosis selected from the group consisting of
gonarthrosis, coxarthrosis and spondylarthrosis.

8. A method according to claim 1, wherein said subject is suffering from
moderate to severe arthrosis pain.

9. A method according to claim 1, wherein said pain is selected from the
group consisting of impact pain, weight-bearing pain, fatigue pain,
periarticular pain caused by pressure, radiating pain, rest pain after
remaining in the same position for a long period, continuous pain,
spontaneous pain, pain on movement, night pain, muscle pain, pain in
extremities and bone pain as spontaneous and rest pain.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001]This application is a continuation of application Ser. No.
12/118,231, filed May 9, 2008 and now abandoned. Priority is claimed
based on Federal Republic of Germany patent application no. DE 10 2007
022 790.8, filed May 11, 2007.

BACKGROUND OF THE INVENTION

[0002]The invention relates to the use of axomadol for the treatment of
pain in the case of arthrosis.

[0003]Arthrosis (osteoarthritis, arthritis deformans) is the most
widespread joint disease in humans. It is a dynamic, but slowly
progressive degenerative disease of the cartilage and other joint tissue,
primarily in older individuals, with intermittent inflammation episodes.
It can be distinguished from other rheumatic diseases because of the
absence of inflammation parameters, the restricted mobility, short-term
joint stiffness and radiological indications.

[0004]Arthrosis or wear on a joint is joint damage that starts with
degeneration of the cartilage of the joint. In severe cases, it
ultimately results in metaplastic processes in the adjacent bone, which
destroys the surface of the joint. Therefore, the effects of the disease
are pain and stiffness of the joint with restrictions in movement. The
joints can become deformed and ultimately become completely ossified.
Arthrosis is generally a slowly progressing process. The cartilage layer
subsequently firstly thickens and the chondrocytes become metabolically
more active. Changes in the subchondral trabecula lead to reduced
pressure relief by the spongy bone. The regenerative tissue is more
heavily stressed and as the disease progresses the balance changes
towards destruction. A narrowing of the joint cavity becomes visible
through radiology and osteophytes are formed at the edges. For further
details, reference can be made in full, for example, to D. Hoffler et
al., Therapy Recommendations of the Drug Commission of the German Medical
Association, drug prescription in practice, "Degenerative Joint
diseases", 2nd edition 2001; and H. Broll et al., CliniCum, special
edition September 2001, Consensus Statement, "Arthrosis, Diagnosis &
Therapy".

[0005]In principle, all joints can be affected by arthrotic changes.
However, those most affected are the knee joints (gonarthrosis) and hip
joints (coxarthrosis), which carry a substantial weight load. The disease
also frequently occurs in the small joints of the spine
(spondylarthrosis) and also in the finger joints. According to ICD-10
arthrosis of the hip and of the knee are defined as primary cartilage
diseases, which are associated with painful restrictions in movement
(impact pain, weight-bearing pain) or walking disabilities. Inflammation
such as synovitis can be established, but does not have to be.

[0006]Principal and early symptoms of arthrosis are pain (early triad:
impact pain, fatigue pain, weight-bearing pain; late triad: continuous
pain, night pain, muscle pain). They are accompanied by restrictions in
movement, sensitivity to weather changes, crepitation. The causes of pain
in the case of arthrosis principally result from irritations in
periarticular tendon and ligament attachments, secondary inflammation,
joint capsule expansion, discharge as a result of irritation, increased
pressure in the subchondral bone and microfractures.

[0007]In early stages pain only occurs when bearing weight and eases again
after a few minutes upon continued movement, e.g. during walking for
longer periods. If inflammation additionally occurs, the typical
complaints of activated arthrosis are evident: the joint is painful, it
feels warm and is swollen. Mobility is restricted. The inflammation often
subsides without treatment. This explains the generally intermittent
course of arthrosis: phases of severe pain and restriction to movement
alternate with phases of little pain and good mobility. As the attrition
signs progress further one pain phase will be followed more quickly by
another. Finally, the pain will remain constant.

[0014]To evaluate the success of a specific therapy, the European League
Against Rheumatism (EULAR) recommends the Lequesne Index, i.e. the global
evaluation by the physician and the pain assessment of the patient.
Besides the assessment of swelling, reddening and pressure resistance of
the joint, the FDA recommends assessment of the pain and function by
means of the Western Ontario McMaster Universities Osteoarthritis Index
(WOMAC) and the Lequesne Index. For drugs used to treat the symptoms of
arthrosis, the Osteoarthritis Research Society recommends the scales of
the WOMAC pain score as main target criterion and as secondary target
criterion the movement restriction score of WOMAC or the Lequesne Index,
and additionally the global evaluation by the physician and patient.

[0022]Opioid analgesics are not routinely part of the repertoire in the
drug treatment of arthrosis, but are unavoidable in certain situations.
However, conventional opioid analgesics exhibit significant side-effects
in some cases, in particular constipation, nausea, vomiting, headaches,
sedation, tiredness, respiratory depression, allergies and occasionally
drop in blood pressure. These side-effects make any long-term therapy of
chronic pain in arthrosis difficult. Therefore, treatment with
conventional opioid analgesics is generally only indicated after all
other therapeutic possibilities have been exhausted, e.g. in patients who
cannot be operated on, but suffer from extreme rest pain that does not
respond to other analgesically active substances.

[0023]There is a need for alternative pharmacotherapeutic methods of
treatment for arthrosis, which are distinguished by an effective
alleviation of pain and an improved side-effect profile.

SUMMARY OF THE INVENTION

[0024]Therefore, it is an object of the invention to find compounds that
are effective in the alleviation of pain in arthrosis and have advantages
over conventional analgesics.

[0025]These and other objects are achieved by the invention as described
and claimed hereinafter.

[0026]The invention relates in particular to the use of axomadol for the
treatment of pain in the case of arthrosis.

[0027]It has surprisingly been found that axomadol combines an excellent
efficacy in the treatment of pain in arthrosis and a reduced side-effect
spectrum. Moreover, it has been found that in the chronic inflammation
pain model, axomadol shows a better analgesic efficacy compared to
conventional analgesics such as morphine, oxycodone and tramadol, for
example.

[0028]Axomadol, i.e.
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-d-
iol, is a synthetic, centrally active analgesic, which is effective in the
treatment of moderate to severe, acute or chronic pain. Axomadol can be
used in the form of its free base or as a salt or solvate.

[0029]U.S. Pat. No. 5,733,936 (=EP 753,506) describes the synthesis of
axomadol and experiments on its analgesic efficacy in the tail-flick test
in mice. The stereoselective synthesis of axomadol by means of enzymatic
racemate resolution of the corresponding ester precursor is known from
U.S. Pat. No. 7,168,937 (=WO 01/57232). US application no. 2004/029878
(=WO 02/43714) discloses axomadol for the treatment of increased need to
urinate or urinary incontinence. US application no. 2004/242617 (=WO
03/024444) describes that an active agent combination containing axomadol
and a muscarine antagonist can also be used to treat urinary
incontinence. US application no. 2005/176790 (=WO 02/067916) describes
the solution behavior of axomadol hydrochloride salt and the solubility
of axomadol saccharinate in water. US application no. 2006/121113 (=WO
2005/009329) discloses the pharmaceutical formulations of axomadol with
delayed active agent release.

[0030]As used in this application, the term "axomadol" means
(1RS,3RS,6RS)-6-dimethyl-aminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3--
diol, its pharmaceutically compatible salts and/or solvates.

[0032]In a preferred embodiment, the medication is a solid drug form. The
medication is preferably manufactured for oral administration. However,
other forms of administration are also possible, e.g. for buccal,
sublingual, transmucosal, rectal, intralumb al, intraperitone al,
transdermal, intravenous, intramuscular, intragluteal, intracutaneous and
subcutaneous administration.

[0033]Depending on the configuration, the medication preferably contains
suitable additives and/or adjuvants. Suitable additives and/or adjuvants
in the sense of the invention include all substances known to persons
skilled in the art for use in the preparation of galenic formulations.
The choice of these adjuvants and also the quantities to be used are
dependent on how the medication is to be administered, i.e. orally,
intravenously, intraperitoneally, intradermally, intramuscularly,
intranasally, buccally or locally.

[0034]Preparations suitable for oral administration include those in the
form of tablets, chewable tablets, lozenges, capsules, granules, drops,
liquids or syrups, and those suitable for parenteral, topical and
inhalatory administration are solutions, suspensions, easily
reconstituted dry preparations and sprays. A further possibility is
suppositories for rectal administration. Examples of suitable
percutaneous forms of administration include administration in a depot in
dissolved form, a patch or a plaster, possibly with the addition of
agents promoting skin penetration.

[0038]The production of these medicaments and pharmaceutical compositions
is carried out using means, devices, methods and processes that are well
known in the art of pharmaceutical technology, as described, for example,
in "Remington's Pharmaceutical Sciences", A. R. Gennaro, 17th ed., Mack
Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters
76 to 93.

[0039]Thus, for example, for a solid formulation such as a tablet, the
active substance of the drug can be granulated with a pharmaceutical
carrier substance, e.g. conventional tablet constituents such as
cornstarch, lactose, saccharose, sorbitol, talc, magnesium stearate,
dicalcium phosphate or pharmaceutically acceptable rubbers, and
pharmaceutical diluents such as water, for example, in order to form a
solid composition that contains the active substance in a homogenous
dispersion. Homogenous dispersion is understood here to mean that the
active substance is uniformly dispersed throughout the composition, so
that this can be readily divided into identically effective standard dose
forms such as tablets, capsules, lozenges. The solid composition is then
divided into standard dose forms. The tablets or pills can also be coated
or otherwise compounded to prepare a slow release dose form. Suitable
coating agents include polymeric acids and mixtures of polymeric acids
with materials such as shellac, cetyl alcohol and/or cellulose acetate,
for example.

[0040]The quantities of axomadol to be administered to patients vary
depending on the weight of the patient, the type of application and the
severity of the illness. In a preferred embodiment, the medication
contains axomadol in a quantity of 10 to 2000 mg, more preferred 15 to
1000 mg, and still more preferred 20 to 500 mg, based on the free base.

[0041]Axomadol can be released slowly from preparations that can be
administered orally, rectally or percutaneously. The medication is
preferably manufactured for administration twice daily (bid), or three
times daily, the twice daily administration (bid) being particularly
preferred. A slow release of axomadol can be achieved, for example, by
retardation using a matrix, a coating or osmotically active release
systems (cf. US 2006/121113, for example).

[0042]In a preferred embodiment: [0043]the medication is manufactured
for oral administration; and/or [0044]the medication is a solid and/or
compressed and/or film-coated drug form; and/or [0045]the medication
releases axomadol slowly from a matrix; and/or [0046]the medication
contains axomadol in a quantity of 0.001 to 99.999% by wt., more
preferably 0.1 to 99.9% by wt., still more preferably 1.0 to 99.0% by
wt., even more preferably 2.5 to 80% by wt., most preferably 5.0 to 50%
by wt. and in particular 7.5 to 40% by wt., based on the total weight of
the medication; and/or [0047]the medication contains a pharmaceutically
compatible carrier and/or pharmaceutically compatible adjuvants; and/or
[0048]the medication has a total mass in the range of 25 to 2000 mg, more
preferred 50 to 1800 mg, still more preferred 60 to 1600 mg, more
preferred 70 to 1400 mg, most preferred 80 to 1200 mg and in particular
100 to 1000 mg; and/or [0049]the medication is selected from the group
consisting of tablets, capsules, pellets and granules.

[0050]The medication can be provided as a simple tablet or as a coated
tablet (e.g. as film-coated tablet or lozenge). The tablets are usually
round and biconvex, but oblong forms are also possible. Granules,
spheres, pellets or microcapsules, which are contained in sachets or
capsules or are compressed to form disintegrating tablets, are also
possible.

[0051]Medications containing at least 0.001 to 99.999% by wt. axomadol, in
particular low effective doses, are preferred to avoid side-effects. The
medication preferably contains 0.01% by wt. to 99.99% by wt. axomadol,
more preferred 0.1 to 90% by wt., still more preferred 0.5 to 80% by wt.,
most preferred 1.0 to 50% by wt. and in particular 5.0 to 20% by wt.

[0052]It is particularly preferred if the medication is in a form for oral
administration that is configured for twice daily application and
contains axomadol in a quantity of 10 to 2000 mg based on the free base.

[0053]Axomadol exhibits a pronounced antihyperalgesic efficiency, which
has been determined in the Complete Freund's Adjuvant (CFA) animal model.

[0054]According to the invention, axomadol is used for the treatment of
pain in the case of arthrosis. The arthrosis is preferably selected from
the group comprising gonarthrosis, coxarthrosis and spondylarthrosis.

[0055]The painful arthrosis is preferably an arthrosis in accordance with
the ICD-10 (International Classification of Diseases and Related Health
Problems, WHO edition, preferably 2007). The arthrosis is preferably
selected from polyarthrosis [M15], coxarthrosis [M16], gonarthrosis
[M17], arthrosis of the first carpometacarpal joint [M18], other
arthrosis [M19] and arthrosis of the spine [M47]. The indications given
in brackets relate to the nomenclature used in the ICD-10.

[0057]If the arthrosis in question is coxarthrosis [M16], then this is
preferably selected from the group comprising bilateral primary
coxarthrosis [M16.0], other primary coxarthrosis (unilateral or
unspecified) [M16.1], bilateral coxarthrosis resulting from dysplasia
[M16.2], other dysplastic coxarthrosis (unilateral or unspecified)
[M16.3], bilateral posttraumatic coxarthrosis [M16.4], other
posttraumatic coxarthrosis [M16.5] (unilateral or unspecified), other
bilateral secondary coxarthrosis [M16.6], other secondary coxarthrosis
(unilateral or unspecified) [M16.7] and coxarthrosis, not further
specified [M16.9].

[0058]If the arthrosis in question is gonarthrosis [M17], then this is
preferably selected from the group comprising bilateral primary
gonarthrosis [M17.0], other primary gonarthrosis (unilateral or
unspecified) [M17.1], bilateral posttraumatic gonarthrosis [M17.2], other
posttraumatic gonarthrosis [M17.3] (unilateral or unspecified), other
bilateral secondary gonarthrosis [M17.4], other secondary gonarthrosis
(unilateral or unspecified) [M17.5] and gonarthrosis, not further
specified [M17.9].

[0059]If the arthrosis in question is arthrosis of the first
carpometacarpal joint [M18], then this is preferably selected from the
group comprising bilateral primary arthrosis of the first carpometacarpal
joint [M18.0], other primary arthrosis of the first carpometacarpal joint
(unilateral or unspecified) [M18.1], bilateral posttraumatic arthrosis of
the first carpometacarpal joint [M18.2], other posttraumatic arthrosis of
the first carpometacarpal joint [M18.3] (unilateral or unspecified),
other bilateral secondary arthrosis of the first carpometacarpal joint
[M18.4], other secondary arthrosis of the first carpometacarpal joint
(unilateral or unspecified) [M18.5], and arthrosis of the first
carpometacarpal joint, not further specified [M18.9].

[0060]If the arthrosis in question is other arthrosis [M19], then this is
preferably selected from the group comprising primary arthrosis of other
joints (primary arthrosis, unspecified) [M19.0], posttraumatic arthrosis
of other joints (posttraumatic arthrosis, unspecified) [M19.1], other
secondary arthrosis (secondary arthrosis, unspecified) [M19.2], other
further specified arthrosis [M19.8], and arthrosis, not further specified
[M19.9].

[0061]Axomadol is preferably used to treat moderate to severe pain. In
preferred embodiments, the pain may be selected from the group consisting
of impact pain, weight-bearing pain, fatigue pain, periarticular pain
caused by pressure, radiating pain (e.g. knee pain in the case of
existing coxarthrosis), rest pain after remaining in the same position
for a long period, continuous pain, spontaneous pain, pain on movement,
night pain, muscle pain, pain in extremities and bone pain as spontaneous
and rest pain. The pain is preferably hyperalgesia or allodynia.
Hyperalgesia is preferably induced thermally or mechanically.

[0062]Even if the medications according to the invention only exhibit
slight side-effects, it can be advantageous, for example, in order to
avoid specific forms of dependency, to also use morphine antagonists, in
particular naloxone, naltrexone and/or levallorphan, besides axomadol.

[0063]The invention additionally relates to a method for treating pain in
the case of arthrosis, in which axomadol is administered to a patient in
a pharmaceutically effective quantity.

[0064]The following examples are intended to illustrate the invention in
further detail, but should not be interpreted as restrictive.

EXAMPLES

1. Clinical Studies

[0065]Two studies with a respective treatment period of 4 weeks were
conducted to determine the efficacy and safety of axomadol in patients
with moderate to severe chronic pain as a result of osteoarthritis
(arthrosis, OA) of functional class I-III. Both studies had a randomised,
multicentric, double blind, double dummy, placebo- and actively
controlled parallel group configuration.

[0066]Patients who were treated with axomadol exhibited a clinically
significant decrease in pain intensity after 4 weeks.

[0067]In both studies over the entire study period, undesirable effects
occurred more frequently in the patient groups treated with active
substance than in the patient groups, to which the placebo was
administered. These undesirable effects are generally typical for
centrally active analgesics.

Study A:

[0068]In this study, patients with OA of the hip or knee were divided into
5 groups. Different daily doses of axomadol were administered to the
patients of 3 of these groups (44, 66 and 110 mg each twice daily based
on the free base), one group was given tramadol (100 mg twice daily) and
one group was treated with a placebo twice daily.

[0069]At each assessment time, a decrease in the pain intensity compared
to the baseline pain was observed in all patient groups. In the full
analysis set on day 29 a clinically relevant decrease in pain intensity
was observed in the patient groups treated with axomadol. This
improvement was not observed in the tramadol and placebo group.

[0070]A clinically relevant decrease in pain intensity in the per protocol
set could be demonstrated dependent on dosage (higher efficacy at the
higher dose) and the results of the patient group that was given 110 mg
axomadol twice daily were statistically significant (p<0.05) compared
to the placebo group.

[0071]The instance of the most frequent undesirable effects was higher in
the patient group that received 110 mg axomadol hydrochloride twice daily
than in every other treatment group. The most frequent undesirable
effects were nausea, constipation, excessive sweating, dizziness,
vomiting, headache, dry mouth and drowsiness.

Study B:

[0072]In this study, patients with OA of the knee were divided into 4
groups. Two of the patient groups received different doses of axomadol
hydrochloride: 100 mg and 150 mg based on the free base, twice daily in
each case after a titration period of 2 weeks, in which the dose of
axomadol was increased on a weekly basis. A further patient group was
given oxycodone CR (20 mg twice daily) after a titration period, in which
oxycodone CR was increased from 10 mg to 20 mg twice daily. A further
group was given a placebo twice daily.

[0073]Analysis of the average pain intensity of the last 24 hours on day
29 for the patient group given 100 mg axomadol twice daily showed a
statistically significant difference (p=0.0190) compared to the placebo
in the full analysis set.

[0074]In the per protocol set, both axomadol groups (p=0.0068 for the 100
axomadol group and p=0.0079 for the 150 mg axomadol group) as well as the
oxycodone group (p=0.0154) showed a statistically significant difference
for the primary endpoint compared to the placebo group. Different
secondary endpoints confirmed these results for the full analysis set and
also for the per protocol set.

[0075]In study B more undesirable effects arose in the three active groups
than in the placebo group. These undesirable effects were generally
slight to moderate in most cases for the axomadol groups. However, the
frequency of undesirable side-effects, which caused individual patients
to discontinue the study, was twice as high in the oxycodone group (31.5%
of patients) as in the two axomadol groups (16.3% in the 100 mg group and
17.7% in the 150 mg group). The most frequent undesirable effects were
constipation, nausea, vomiting and dry mouth.

2. Antihyperalgesic Effect in the Chronic Inflammation Pain Model

[0076]The test to determine the antihyperalgesic effect of axomadol in
chronic inflammation pain was conducted on rats in the Complete Freund's
Adjuvant animal model (CFA).

[0077]A model for chronic inflammation represents the monoarthritis
triggered by the Complete Freund's Adjuvant (CFA). By injecting a small
quantity of CFA (100 μg M. tuberculosis) into the back paw a local
inflammatory reaction restricted in time to 2-4 weeks occurred. The
hyperalgesia occurring in parallel (hence the name CFA-hyperalgesia
(CFA-HA) used hereafter) to mechanical or thermal stimuli is restricted
to the inflamed paw.

[0078]Sprague Dawley rats from a commercial breeder (Janvier, Belgium)
having a weight of 140-160 g were used as test animals. The CFA-HA was
induced in rats by subplantar injection of CFA (100 μl of the 1 mg/ml
mycobacteria (heat-killed M. tuberculosis)/oil suspension (IFA; Difco))
into the back paw (ipsilaterally). The injection day was defined as day 0
(d 0).

[0079]Hyperalgesia to a mechanical tactile stimulus was detected by means
of an electronic von Frey measuring instrument (Somedic Electronic von
Frey System, Somedic Sales AB, Horby, Sweden). The paw was stimulated by
subplantar application. To quantify the sensitivity of both the ipsi- and
the contralateral paw to the mechanical stimulus, the paw pull-away
threshold was given in grams of applied pressure. The median was formed
from the four measured values per paw. The pull-away threshold of the
ipsi- and contralateral paw was determined on day 1 after CFA injection
before (=initial value) and at different times (15, 20 and 60 minutes)
after substance dose (measured value). The efficacy of a substance was
calculated as % inhibition of hyperalgesia as follows:

[0080]In total, 10 rats were used in each test animal group. The
mean±SEM was calculated from the medians of the individual animals.
The significance calculation was conducted using the two-factor analysis
of the variance (ANOVA) for repeated measurements. In the case of a
significant treatment effect, a comparison in pairs was conducted at
different measurement times by a Fisher's significance test, followed by
a post hoc Dunnett test. The results were assessed as statistically
significant at p<0.05.

[0081]In order to determine the maximum efficacy, the substance was
administered intravenously (IV) up to the maximum possible dose. The
highest possible dose was defined as the dose that still exhibited no
side-effects influencing the measurements and no severe antinociceptive
effect on the untreated paw and a further increase in dose cased these
effects. The maximum efficacy was determined based on the maximum
achievable inhibition of hyperalgesia that could be reached in a dose
range, which 1. did not induce any overlap with antinociceptive effects
on the contralateral paw and/or 2. did not induce any side-effects to
such an extent as to influence interpretation of the measured values.

Results:

[0082]Axomadol significantly reduces CFA-induced hyperalgesia. A maximum
antihyperalgesic effect of 40% was reached after intravenous application
of 10 mg/kg axomadol-HCl. Higher doses led to a decrease in the
antihyperalgesic effect to 9% and also an overlap with an additional
antinociceptive effect.

[0085]The foregoing description and examples have been set forth merely to
illustrate the invention and are not intended to be limiting. Since
modifications of the described embodiments incorporating the spirit and
substance of the invention may occur to persons skilled in the art, the
invention should be construed broadly to include all variations within
the scope of the appended claims and equivalents thereof.